Preparation of phenolic ethylenediaminepolycarboxylic acids



tates atene Unite are reacted to yield a solution of the desired product,- 2824128 according to the following reaction scheme: PREi ARATION F PHENOLIC ETHYLENEDI- OH AMINEPOLYCARBOXYLIC ACIDS 5 X Martin Dexter, Cranston, R. L, assignor to Geigy Chemi- 2 O O a O zO i i cal Corporation, New York, N. Y., a corporation of X X (3:0 Delaware g: N8

N0 Drawin A lication Febru 3 1956 Seri i No. 563,183 m B 3 Claims. (Cl. 260-519) x -CHNH-CH2CHr-NHCH K 0 0 0:0 +2H2O X X X- X This invention relates to a novel and versatile pro- 0N8 N cedure for the manufacture of organic compounds-- X ethylene-bis-(a-imino-o-hydroxyphenylacetic acid) and derivatives-that are capable of chelating polyvalent metal (I) ions in neutral and alkaline solutions. Extensive field wherein X y be hydrogen, halogen, Sulfonle field, trials have shown that these compounds are remarkably in yL y y y effective in the correction of iron chlorosis in plants The reaction is advantageously baffled but at a growing in alkaline soils. With the use of these chelating Perawre between and and at a P between agents increased crop yields can be obtained and sub- 3 and A water-miselble Solvent Such as y marginal agricultural areas restored to greater producetbyl isbpfepyleleohbl y be used to enhance the tivity. It has also been shown that chelating agents in solbbiliiy of some of the Substituted Phebe1S in the wide use such as ethylenediamine tetraacetic acid and aetlon mixturehydroxyethylethylenediaminetriacetic acid are relatively In "1051 eases the desired ehelafing agent can be p i fi tw cipitated from solution by acidification of the reaction o f h major deterrents to h id d use of mixture to a pH between 4 and 5. It is usually desirable these compounds in combating trace metal deficiencies to remove unl'eaeted Phenolic compounds y Solvent in agriculture has been the expensive method of manutI'ZlCilOll Oi steam distillation pI'lOl to precipitation. facture. Despite their effectiveness they could be used It is Possible to use Sodium dieblorbaeelate in Place to economic ad antage only on high priced crops. of sodium glyoxylate in the above synthesis. In this Their synthesis, as heretofore practiced, can be sumcase it is ry, however, to add two moles of base marized as follows: for each mole of sodium dichloroacetate used in order Two moles of salicylaldehyde (oraderivative of salicylto maintain the desired degree of alkalinity during the aldehyde) is reacted with one mo] of ethylenediamine to l'efleiionyield a Schiff base. The Schiff base is then reacted with The Overall reaction using Sodium dichloroacetate y two moles of hydrogen cyanide to give a dinitrile. Cone Written HS o s:

2 2CHCl: H N-CHQCHr-NH 4N5OH ---e x x ,f k (ilNa on on X CH--NHCHgCHg-NHCH X 4NaCl 4H1O X X a g X X Na Na i; X

(H) centrated hydrochloric acid is then used to hydrolyze the Examination of Equations I and II shows that identical nitrile and to yield the dihydrochloride of the desired chelating agents are produced in both reactions. product. Representative presently-preferred embodiments of the The high price of salicylaldehyde, the number of chempresent invention are set forth in the following illustraical manipulations necessary and low overall yield contive examples wherein. unless otherwise indicated, the tribute to making these products expensive. parts and percentages are by weight. The relationship A primary object of the present invention is the embetween parts by volume and parts by weight is the same bodiment of a synthesis which is free of the afore-enumas th etween m i iters and g erated defects. According to the present invention, the EXAMPLE} said chelatmg agents can be prepared by a one-step re- 5 a t action from readily available intermediates, whereby the Y 'Q aforesaid object is realized. Thus, sodium glyoxylate,

ethylenediamine, and phenol (or a substituted phenol); v To a solution of 43 parts by volume 0i sodium gly oxylate, containing 9.8 parts of 100% material, is added 3.5 parts of 86.8% ethylenediamine, 12.2 parts of 4- hydroxyl-1,3-dimethylbenzene and 50 parts by volume of methanol. The mixture is heated for 7 hours at 70 C. The pH is maintained at 8.5 by the dropwise addition of 2 parts of 50% aqueous sodium hydroxide solution dur ing the reaction.

Unreacted dimethylphenol is extracted with ethyl ether after cooling to room temperature (about 20 to 30 C.) and diluting with 50 parts by volume of water. The productethylene bis (a imino 2 hydroxy 3,5- dimethylphenylacetic acid)is precipitated by acidification to pH 4.5 with dilute HCl, filtered from solution, and washed successively with water and acetone. The yield after drying is 13 parts or 62.5% of theory.

Electrometric titration with perchloric acid in acetic acid solution gives a neutral equivalent of 199. The theoretical value is 208. The iron chelate is bluish red.

EXAMPLE 2 Ethylene-bis-(a-imin-2-hydroxy-5-methylphenylacetic acid) The reaction is caried out as in Example 1 except that 21.6 parts of p-cresol are used instead of the 4-hydroxy-l,3-dimethylbenzene.

The yieldethylene-bis-(a-imino-2-hydroxy-5 methylphenylacetic acid)is 12.4 parts; 64% of theory. Neutral equivalent (determined as in Example '1,-las t paragraph) 188.5; calculated 194.

EXAMPLE 3 Ethylene-bis-(a-imino-Z-hydroxy-d,S-dim'ithyiphenylacetic acid) To a reaction vessel equipped with thermometer, glass and calomel electrodes, agitator, and reflux condenser are added 52.5 parts of dichloroacetic acid and 25 parts of Water. The dichloroacetic acid is neutralized by 'the addition of 69 parts by volume of 6.2 N aqueous sodium hydroxide solution. External cooling is used to keep the temperature below 35 C. To this solution is then added 86.4 parts of p-cresol, 50 parts by volume of methanol and 13.9 parts of an 87% aqueous solution of ethylenediamine.

The temperature is raised to approximately 90- C. and held at that temperature -for 3' hours and 1-5 minutes. During the reaction 6.2 N aqueous sodium hydroxide solution is added to maintain a pH of 9.5. The mixture is then cooled and the pH lowered to 4.2 by the addition of 6 N hydrochloric acid. The productethylene-bi's-(a ing is used during the neutralization.

imino-2-hydroxy-3,S-dimethylphenylacetic acid)is filtered, washed thoroughly with acetone and water and dried at 100 C. The yield is 41 parts, 53% of theory. The neutral equivalent, determined as in Example 1, is 182. Calc. value 194.

EXAMPLE 4 Ethylene-bis-( ot-imino-Z-hydroxy-S-chloro- V phenylacetic acid) A solution of 5 1.5 'parts of dichloroacetic acid in 25 parts by volume of water is neutralized with .68 parts by volume of 6 N aqueous sodium hydroxide solution. Seventy-seven parts of.p-chlorophenol,40 parts by-volume of methanol and 12.1 parts of ethylenediamine are added EXAMPLE 5 Ethylene-bisa-imino-2-hydroxy-5-tertiarybutylphenylacezic acid) A solution of 52.5 parts of dichloroacetic acid and 25 parts by volume of water is neutralized with 32 parts by volume of 6 N aqueous sodium hydroxide solution. To this mixture is added parts of p-tcrtiary-butylphenol, 13.9 parts of 87% ethylenediamine and 160 parts by volume of methanol. The'mixture is heated at C. for seven hours. During the reaction 195 parts by volume of 6 N aqueous sodium hydroxide solution is added to maintain a pHof 9.5.

Methanol is removed from the reaction mixture by distillation until the vapor temperature reaches 100 C. After cooling to 30 C.,-the mixture is extracted with several portions of ethyl ether to remove unreacted ptertiary-butylphenol. The product-ethylenc-bis-(ct-imin0-2-hydroxy-5-tertiary-butylphenylacetic acid)is precipitated from the aqueous phase by'acidification with 6 N hydrochloricfacid, filtered; Washed successively with water and acetone, and dried at 100 C.

The yield is 63.51'parts; 67.3% of theory. The neutral equivalentbynon-aqueous titration with perchloric acid is 213; calculated 2'36.

EXAMPLE 6 EthyIne-bis a-iminO-Z-hydrOxy-S-Sulfonic 'phe'nyla'cetic acid) To a reaction flask are added 232 parts of a 45% aqueous solution of phenol sulfonic acid and 51.5 parts of dichloroacetic acid. Approximately 196 parts by volume of 6.2 N aqueous sodium hydroxide solution is used to raise the pH of the solution'to 7. External cool- 13.9 parts of ethylenediamine (87%) is then added and the mixture heated at 90 C. for 5 hours. 170 parts by volume of 6.2 N aqueous sodium hydroxide solution is used to maintain the pH at 9.5. Anassay of the solution bydetermining its ability to chelate ferric iron shows a yield of productethylene-bis-(a-imino-2-hydroxy-5 sulfonic phenylacetic acid)of 69%. p

. EXAMPLE 7 V Ethylene-bis-(a-imino-Z-hyldroxyphenylacetic acid) v The reaction is carried out in a manner similar to that of Example 1 except that 10.3 parts of phenol are used "in place of-12.2parts of 4-hydroxy 1,S-dimethylbenzene.

EXAMPLE 8 Ethylene-bisa-imino-2-hydr0xy-5-carb0xyphenylacetic acid) A mixture of 110.5 parts of p-hydroxybenzoic acid, 50 parts by volume of Water and 105 parts of dichloroacetic acid is neutralized with 268 parts .by volume of 5.9 N aqueous sodium hydroxide. External cooling is used to keep the temperature of the reaction mixture below '35" C. 27.7 parts of 86.8% ethylenediamine are added and the temperature raised to -100 C. and maintained at that temperature for 3 /2 hours. 6 N aqueous sodium hydroxide solution is added during the reaction to maintain the pH at 9.5.

The mixture is cooled to room temperature and acidifie'd to apt-I olf 4 with6 N hydrochloric'acid. The reacetone,

Yield of ethylene-bis-(u-iminQ-Z-hydroXy-S-carboxyphenylacetic acid)=101 parts. Neutral equivalent by perchloric-acetic acid titration is 231; calculated 224.

EXAMPLE 9 Ethylene-bis-(a-imino-Z-hydrxy-5-octylphenylacetic acid) To a reaction vessel equipped with a thermometer, glass and calomel electrodes, agitator and reflux condenser are added 52.5 parts of dichloroacetic acid and 25 parts of water. The dichloroacetic acid is neutralized by the addition of 65 parts by volume of 6 N aqueous sodium hydroxide solution. External cooling is used to prevent the temperature from exceeding 50 C. To this solution are added 14 parts of 86% ethylenediamine. The temperature of the reaction mixture is raised to 85 C. and the pH is maintained at 10 by the addition of 64 parts of 50% aqueous sodium hydroxide solution. The time for this reaction is about one hour. To the reaction mixture is added 82.5 parts of octylphenol and 300 parts by volume of methanol. The condensation is carried out by heating for 17 hours at 75 C.

Methanol is distilled from the reaction mixture until the internal temperature rises to 85 C. The crude product is acidified to pH 4 by the addition of 40 parts of 6 N hydrochloric acid. After cooling, the supernatant liquors are decanted and the product granulated by the addition of acetone.

The yield of dry materialethylene-bis-(a-imino-Z-hydroxy-S-octylphenylacetic acid)is 97.5 parts.

The neutral equivalent by titration with perchloric acid in acetic acid is 253. The calculated value is 292. The product forms a red-purple colored iron complex.

The eifectiveness of the chelating agents of the present invention in making iron available to plants is illustrated in the following comparative runs, using calcareous Utah soil. The pH of this soil was 7.8. Lima bean seeds planted in pint containers were treated with 10 ml. of a solution containing mg. of radioactive iron and an equivalent quantity of chelating agent. The Fe content of the iron was equivalent to 5 microcuries. The lima bean plants were allowed to grow until the second trifoliate leaves appeared. They were then harvested and examined for radioactivity by means of a scintillation counter. The amount of radioactivity is a direct measure of the iron uptake of the plant. The following table shows the relative amounts of iron uptake as indicated by the level of radioactivity:

Chelating agent:

(a) None (control) 1 (b) Ethylenediamine telraacetic acid 1 (c) Versenol (hydroxyethyl ethylenediaminetriacetic acid) 2.15 (d) Ethylene-bis (a-imino-2-hydroxy-5-methylphenylacetic acid) 40.7

wherein X is selected from the group consisting of H, alkyl, chlorine, carboxyl and sulfo, with ethylenediamine and with a member selected from the group consisting of sodium glyoxylate and sodium dichloroacetate.

2. A process for the preparation of an ethylene-bis-(aimino-hydroxyphenylacetic acid), which comprises reacting, at a temperature between about and about C. and at a pH between about 8 and about 10, a compound of the formula wherein X is selected from the group consisting of H, alkyl, chlorine, carboxyl and sulfo, with ethylenediamine and with sodium glyoxylate.

3. A process for the preparation of an ethylene-bis- (a-imino-hydroxyphenylacetic acid), which comprises reacting, at a temperature between about 70 and about 100 C. and at a pH between about 8 and about 10, a compound of the formula wherein X is selected from the group consisting of H, alkyl, chlorine, carboxyl and sulfo, with ethylenediamine and with sodium dichloroacetate.

No references cited. 

1. A PROCESS FOR THE PREPARATION OF AN ETHYLENE-BIS(A-IMINO-HYDROXYPHENYLACETIC ACID), WHICH COMPRISES REACTING AT A TEMPERATURE BETWEEN ABOUT 70* AND ABOUT 100* C. AND AT A PH BETWEEN ABOUT 8 AND ABOUT 10, A COMPOUND OF THE FORMULA 